Oncothyreon Inc., a biotechnology company specializing in the development of innovative therapeutic products for the treatment of cancer, has initiated an investigator-sponsored trial of ONT-380 in combination with trastuzumab (Herceptin) in patients with brain metastases from HER2+ breast cancer. The trial is being conducted under the sponsorship of the Dana-Farber Cancer Institute, Boston, Massachusetts. ONT-380 (also known as ARRY-380) is an orally active, reversible and selective small-molecule HER2 inhibitor being developed by Oncothyreon in collaboration with Array BioPharma Inc., Boulder, Colorado.

The phase 1 trial is a dose-escalation trial in up to 50 patients. The primary objectives are to determine the maximum-tolerated dose and recommended phase II dose and schedule of ONT-380 in combination with trastuzumab in patients with HER2+ breast cancer and central nervous system (CNS) metastases. Secondary objectives include CNS objective response rate by both RECIST and volumetric criteria, progression-free survival and overall survival. The study will be conducted in two parallel arms with two dose regimens of ONT-380, either once-daily or twice-daily, in combination with standard dose trastuzumab.

"ONT-380 has demonstrated superior activity, based on overall survival, compared to Tykerb (lapatinib) and to the investigational drug, neratinib, in an intracranial HER2+ breast cancer xenograft model," said Robert L Kirkman, MD, president and CEO of Oncothyreon. "This provides a strong rationale to explore whether ONT-380 can provide benefit to patients with brain metastases, and we are pleased that the Dana Farber Cancer Institute is undertaking this trial."

"CNS metastases, which occur in one-third to one-half of women with metastatic HER2+ breast cancer, remain a significant clinical problem," said Nancy U. Lin, M.D., Principal Investigator of the phase 1 trial and Clinical Director, Breast Oncology, Dana-Farber Cancer Institute. "There is an urgent need for new therapies to treat patients with brain metastases from breast cancer, and we are excited to begin this study of ONT-380.”

ONT-380 is an orally active, reversible and selective HER2 inhibitor. In multiple preclinical tumor models, ONT-380 was well tolerated and demonstrated significant dose-related tumor growth inhibition that was superior to Herceptin and Tykerb. Additionally, in these models, ONT-380 demonstrated synergistic or additive tumor growth inhibition when dosed in combination with the standard-of-care therapeutics Herceptin or Taxotere (docetaxel).

A phase I trial of ONT-380, with both dose-escalation and expansion components, has been completed in 50 patients, 43 of whom had HER2+ metastatic breast cancer. All HER2+ breast cancer patients had progressed on a trastuzumab-containing regimen. In addition, over 80 per cent had been treated with lapatinib, with many having progressed on therapy. In this study, ONT-380 demonstrated an acceptable safety profile; treatment-related adverse events were primarily Grade 1. Because ONT-380 is selective for HER2 and does not inhibit EGFR, there was a low incidence and severity of treatment-related diarrhea, rash and fatigue. Additionally, there were no treatment-related cardiac events or Grade 4 treatment-related adverse events reported. The maximum tolerated dose of ONT-380 established in this Phase 1 trial was 600 mg twice daily (BID). Twenty-two HER2+ breast cancer patients with measurable disease were treated with ONT-380 at doses greater than or equal to 600 mg BID. In this heavily pretreated patient population, there was a clinical benefit rate (partial response [n = 3] plus stable disease for at least six months [n = 3]) of 27 per cent. Notably, two of the patients with partial responses during treatment with ONT-380 had confirmed progressions while on prior lapatinib- and trastuzumab-containing regimens.